Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the U.S., approximately 3-4 million persons are affected by this disease, costing the U.S. economy more than $50 billion per year. The cause(s) of this debilitating neurodegenerative disease is(are) presently unknown. However, a large body of evidence indicates that at least some, if not all, AD cases are due to genetic factors. Genetic analyses of families with multiple cases of early-onset AD has shown that three autosomal dominant genes are responsible for at least some occurrences of the disease. In these families, offspring of affected persons are at 50% risk of inheriting a familial AD (FAD) gene and developing AD. Late-onset FAD (LOFAD) seems to involved other genes and is a more complex disease. Using linkage analysis and other sophisticated statistical genetic methods, the long-range goal of this project is to identify the underlying causes of AD by identify the genes responsible for the genetic forms of this disease. Four genetic loci have been identified which are heritable factors in AD: the amyloid precursor protein (APP) gene, presenilin 1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1, and a susceptibility locus at the ApoE gene/region on chromosome 19. The following Specific Aims of this project address characterizing existing AD genes and mapping new AD loci: 1) Identify and sample new FAD kindreds. 2) Identify the chromosomal regions containing LOFAD loci. 3) Identify chromosomal regions containing genes that modify age of onset of AD in Volga German families with a specific PS2 mutation. 4) Characterize the relationship between ApoE genotypes and FAD in the presence of other covariates. Identification of FAD genes and modifying factors will facilitate establishing the etiology of AD, lead to better diagnostic methods, and potentially provide a rationale for designing therapeutic and preventive measures.